title: CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease.
abstract: The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.
authors.affiliation: Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine,Chapel Hill, NC 27599, USA. jcoghill@e-mail.unc.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Coghill
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Fowler
authors.forename: Michelle L
authors.initials: ML
authors.lastname: West
authors.forename: Leshara M
authors.initials: LM
authors.lastname: Fulton
authors.forename: Hendrik
authors.initials: H
authors.lastname: van Deventer
authors.forename: Karen P
authors.initials: KP
authors.lastname: McKinnon
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Vincent
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Lin
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D039521:CD11c Antigen / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D054401:Receptors, CCR8 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*; D014019:Tissue Donors
chemical_list: D039521:CD11c Antigen; C489319:Ccr8 protein, mouse; D054401:Receptors, CCR8